Editorial note (2026-10-03): historical review from 2016. Experimental animal/cell findings and human associations are distinguished below; they do not establish inevitable psychiatric outcomes or a universal receptor threshold in people. Bibliographic reference 16 was recovered and limited scientific corrections are identified in this edition; the complete cited literature was not clinically reassessed.
Abstract:
Neglect and abuse, particularly during infancy and the early stages of life, can lead to epigenetic regulation of genes involved in stress-response, behavioral disinhibition, and cognitive-emotional systems. This stress induces long-lasting effects on the HPA axis. Objective: Review evidence on neurobiological alterations associated with abuse and neglect. Introduction: Programming of the HPA axis, one of the key mechanisms that contribute to altered metabolism and the response to stress, often involves epigenetic modification of the glucocorticoid receptor (GR) gene promoter, which influences tissue-specific GR expression patterns and response to stressful stimuli. 1 Stress-mediated epigenetic modifications may be more pronounced during the stress-vulnerable, early-life period where brain regions implicated in emotionality and stress reactivity, such as the hippocampus, amygdala, and the prefrontal cortex, are undergoing rapid changes in dendritic density, myelination, and synaptic plasticity. 2,3 Epigenetics is the study of mitotically and/or meiotically heritable changes in gene function that are not explained by changes in DNA sequence. 4 Preclinical5 , epidemiological6 , and clinical studies7 suggest a strong link between exposure to stress, dysregulation of the HPA-axis, and susceptibility to neuropsychiatric illnesses. Methods: Research articles in the PubMed database.
Results: Abuse and neglect in childhood can contribute to neuroendocrine alterations and increase the risk of behavioral difficulties in later life.
Discussion: In response to stress, the hypothalamic paraventricular nucleus (PVN) releases corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP), which enter the hypophyseal portal circulation and stimulate the synthesis and secretion of adrenocorticotropin (ACTH) into the peripheral circulation. ACTH initiates the production and secretion of glucocorticoid from the adrenal cortex. In cases of exposure to trauma or chronic stress, negative-feedback regulation of the HPA-axis becomes disrupted, leading to aberrant glucocorticoid levels that can persist even in the absence of additional stressors. 8 Prenatal stress can alter HPA responses in rats, with sex-specific effects described in reference9. Experimental reduction of GR expression has been used to investigate HPA feedback in mice10 and glucocorticoid-dependent transcription in cell lines11. Editorial note (2026-10-03): these studies do not establish a universal 30–50% reduction threshold causing neuroendocrine, metabolic and immune disorders in people. An epidemiological study that examined hundreds of thousands of patients who were prescribed glucocorticoids for non-psychiatric disorders found a significant increase in cases of depression, suicidal behavior, mania, and panic disorder associated with glucocorticoid therapy.12 Glucocorticoid administration to adolescent animals is capable of inducing loss of DNA methylation and an increase in expression of FKBP5 13 , a chaperone protein and primary regulator of intracellular GR-signaling14, which has been implicated in numerous association studies of depression, bipolar disorder, and PTSD. 15,16 Methylation alterations observed in the glucocorticoid response element (GRE) persisted into adulthood and were associated with anxiety-like behavior17 .
Conclusion: Altered glucocorticoid levels cause deregulation of the HPA-axis negative feedback and disturbances in glucocorticoid signaling, which can have a negative impact on behavior by epigenetic control of genes that regulate mood and neurotransmission. Thereby, early-life adversity increases risk of psychiatric disorders, such as major depressive disorder (MDD) and posttraumatic stress disorder (PTSD),18,19 besides suicide in susceptible individuals by disrupting the development of stable emotional, behavioral and cognitive phenotypes.20
Acknowledgements: Professor Edward Ziff and Professor Elisabete Castelon Konkiewitz
DIANA SEVILHA SALVUCCI, GUILHERME GONÇALVES MARTINS LUGO: UNIVERSIDADE FEDERAL DA GRANDE DOURADOS, UFGD, DOURADOS, MS, BRASIL
References
1. Xiong F, Zhang L. Role of the Hypothalamic-Pituitary-Adrenal Axis in Developmental Programming of Health and Disease. Frontiers in neuroendocrinology. 2013;34(1):27-46. doi:10.1016/j.yfrne.2012.11.002.
2. Jernigan TL, Trauner DA, Hesselink JR, Tallal PA. Maturation of human cerebrum observed in vivo during adolescence. Brain. 1991;114(Pt 5):2037–49.
3. Giedd JN. Structural magnetic resonance imaging of the adolescent brain. Ann N Y Acad Sci.2004;1021:77–85.
4. Russo VEA. Epigenetic mechanisms of gene regulation. Cold Spring Harbor Laboratory Press; Cold Spring Harbor, NY: 1996.
5. Barha CK, Brummelte S, Lieblich SE, Galea LA. Chronic restraint stress in adolescence differentially influences hypothalamic-pituitary-adrenal axis function and adult hippocampal neurogenesis in male and female rats. Hippocampus. 2011;21:1216–27.
6. Clark C, Caldwell T, Power C, Stansfeld SA. Does the influence of childhood adversity on psychopathology persist across the lifecourse? A 45-year prospective epidemiologic study. Ann Epidemiol.2010;20:385–94.
7. Heim C, Newport DJ, Mletzko T, Miller AH, Nemeroff CB. The link between childhood trauma and depression: insights from HPA axis studies in humans. Psychoneuroendocrinology. 2008;33:693–710.
8. Lee R, Sawa A. Environmental stressors and epigenetic control of the hypothalamic-pituitary-adrenal axis (HPA-axis). Neuroendocrinology. 2014;100(4):278-287. doi:10.1159/000369585.
9. McCormick CM, Smythe JW, Sharma S, Meaney MJ. Sex-specific effects of prenatal stress on hypothalamic-pituitary-adrenal responses to stress and brain glucocorticoid receptor density in adult rats.Brain Res Dev Brain Res. 1995;84:55–61.
10. Pepin MC, Pothier F, Barden N. Impaired type II glucocorticoid-receptor function in mice bearing antisense RNA transgene. Nature. 1992;355:725–8.
11. Vanderbilt JN, Miesfeld R, Maler BA, Yamamoto KR. Intracellular receptor concentration limits glucocorticoid-dependent enhancer activity. Mol Endocrinol. 1987;1:68–74.
12. Fardet L, Petersen I, Nazareth I. Suicidal behavior and severe neuropsychiatric disorders following glucocorticoid therapy in primary care. Am J Psychiatry. 2012;169:491–7.
13. Lee RS, Tamashiro KL, Yang X, Purcell RH, Harvey A, Willour VL, Huo Y, Rongione M, Wand GS, Potash JB. Chronic corticosterone exposure increases expression and decreases deoxyribonucleic acid methylation of Fkbp5 in mice. Endocrinology. 2010;151:4332–43.
14. Wochnik GM, Ruegg J, Abel GA, Schmidt U, Holsboer F, Rein T. FK506-binding proteins 51 and 52 differentially regulate dynein interaction and nuclear translocation of the glucocorticoid receptor in mammalian cells. J Biol Chem. 2005;280:4609–16.
15. Binder EB, Salyakina D, Lichtner P, Wochnik GM, Ising M, Putz B, Papiol S, Seaman S, Lucae S, Kohli MA, Nickel T, Kunzel HE, Fuchs B, Majer M, Pfennig A, Kern N, Brunner J, Modell S, Baghai T, Deiml T, Zill P, Bondy B, Rupprecht R, Messer T, Kohnlein O, Dabitz H, Bruckl T, Muller N, Pfister H, Lieb R, Mueller JC, Lohmussaar E, Strom TM, Bettecken T, Meitinger T, Uhr M, Rein T, Holsboer F, Muller-Myhsok B. Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nat Genet. 2004;36:1319–25
16. Willour VL, Chen H, Toolan J, Belmonte P, Cutler DJ, Goes FS, Zandi PP, Lee RS, MacKinnon DF, Mondimore FM, Schweizer B, DePaulo JR, Jr, Gershon ES, McMahon FJ, Potash JB. Family-based association of FKBP5 in bipolar disorder. Mol Psychiatry. 2009;14(3):261–268. doi:10.1038/sj.mp.4002141.
17. Lee RS, Tamashiro KL, Yang X, Purcell RH, Huo Y, Rongione M, Potash JB, Wand GS. A measure of glucocorticoid load provided by DNA methylation of Fkbp5 in mice. Psychopharmacology (Berl)2011;218:303–12.
18. Sullivan PF, Daly MJ, O’Donovan M. Genetic architectures of psychiatric disorders: the emerging picture and its implications. Nat Rev Genet. 2012;13:537–51.
19. Sartor CE, Grant JD, Lynskey MT, McCutcheon VV, Waldron M, Statham DJ, Bucholz KK, Madden PA, Heath AC, Martin NG, Nelson EC. Common heritable contributions to low-risk trauma, high-risk trauma, posttraumatic stress disorder, and major depression. Arch Gen Psychiatry. 2012;69:293–9.
20. Turecki G, Ernst C, Jollant F, Labonté B, Mechawar N. The neurodevelopmental origins of suicidal behavior. Trends Neurosci. 2012;35:14–23.